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Trastuzumab for the treatment of HER2 positive advanced gastric cancer
Appraisal Consultation Document (ACD)
Comments submitted by Dr Patrick Cadigan, RCP registrar on behalf of:
NCRI/RCP/RCR/ACP/JCCO
Comments coordinated by Dr David Watkins
We do not consider that the ACD provides a reasonable interpretation of the
evidence and fails to appreciate the clinical significance of the ToGA trial results in
this patient population.
Clinical Effectiveness – The significance of trastuzumab to this patient population
The ToGA study represents a truly significant advance in the management of this
patient group. The survival benefit in the licensed patient population was greater than
4 months, for a disease with a median survival of less than 12 months, and with a
Hazard Ratio of 0.65. This is the largest survival benefit recorded in a high quality
randomized clinical trial for any single agent or combination in advanced gastric
cancer and represents a major advance in this disease. Oesophagogastric cancer is
considered among the tumour types with the highest level of medical need. The
survival outcomes in this disease are amongst the poorest of all the common cancers
with little progress made over recent decades (figure 1). Modern cytotoxic agents
have failed to result in significant gains and overall survival in this disease setting has
stagnated at 9-11 months over the previous 15 years (figure 2). As such, it is vital
that where there are clear opportunities for progress, as is the case for trastuzumab,
that investment in to improving patient outcomes is made.
Cost Effectiveness – The evaluation of ECX/EOX as a comparator
The use of a triplet chemotherapy regimen comprising epirubicin, platinum and
capecitabine (ECX/EOX) has evolved in the UK over two decades of sequential
randomized controlled clinical trials. ECF was initially developed as a triplet regimen
based on evidence of single agent activity for each individual agent, and in
comparison with the previous triplet regimen in use, rather than as a step-wise
addition of epirubicin to existing doublet regimens. The specific benefit of epirubicin
to the CX/OX doublet has never been robustly studied and hence can not be reliably
estimated. In the cost-effectiveness model the benefit of epirubicin has been
overstated with a Hazard Ratio as significant as 0.77 based on the Wagner metaanalysis1. As indicated at the initial appraisal meeting this meta-analysis was felt to
significantly over state the benefit of epirubicin and its use in cost effectiveness
model is inappropriate. A Hazard Ratio of 0.77 is far in excess of the observed
benefit demonstrated in successive randomized clinical trials for any single
chemotherapy intervention in this disease. The value of the meta-analysis is further
debated given that the included studies used regimens with lower doses and lower
dose-intensity of cisplatin &/or fluoropyrimidine than used in the ToGA comparator
regimens. In addition, none of the studies utilised capecitabine containing regimens
which may influence the relative benefit of epirubicin. Epirubicin is considered to
provide some additional benefit to CF/CX and in the absence of any more active
alternative therapies epirubicin containing triplet regimens should remain the
standard of care in HER2 negative gastric cancer. However for HER2 positive gastric
cancer the addition of trastuzumab to a CF/CX backbone has demonstrated a clear
survival benefit with a favourable toxicity profile and should be the standard of care in
this disease setting.
End-of-life Criteria – Rational for inclusion of the breast cancer population
This submission fails to meet the end–of–life criteria solely because trastuzumab is
already licensed for breast cancer. Herceptin is licensed for both early and advanced
breast cancer, and the median survival of patients with early breast cancer treated
with adjuvant herceptin is of the order of several years. It is surprising and
inappropriate that this patient group should influence the end–of–life treatment
decisions of patients with gastric cancer, a clearly distinct patient population. The
end-of-life rules as applied have the consequence of disadvantaging patients with
rarer tumours, often with more limited therapeutic options and poorer overall survival,
as is the case in gastric cancer. In addition, we believe that, the application of end-oflife criteria in this way results in the nonsensical position where if trastuzumab had
been licensed in gastric cancer prior to breast cancer the outcome of a NICE
appraisal would likely be more favourable. During the committee meeting it was
implied that this situation was acceptable and that the manufacturer would be
expected to in some way support the adoption in rarer indications. We are uncertain
as to how NICE envisage this being facilitated and further consideration and
clarification with regard to the application of the end-of-life criteria appears
necessary. The number of patients the current appraisal will apply to is small and
comfortably within the end-of-life criteria thresholds. Additionally, the availability of
generic formulations of trastuzumab in the medium term will reduce the cost of this
therapy and as such the overall impact on NHS budgets will be modest.
Impact on UK Research Practice
Through undertaking pivotal studies such as OEO22, MAGIC3 and REAL-II4, the UK
has played a central role in shaping international standards of care in
oesophagogastric cancer. Trastuzumab represents a further significant advance in
the treatment of gastric cancer and is a globally accepted standard of care in the
management of HER2 positive disease. As such, we believe that, the rejection of
funding for trastuzumab across England and Wales amounts to a retrograde step for
gastric cancer care in the UK. Furthermore, ongoing academic and commercial
clinical research would be hindered without access to the accepted standard of care
in this patient group. Current research practice is focused on identifying
patient/tumour characteristics associated with response &/or resistance to targeted
therapies, with the aim of improving the cost/benefit ratio of treatment. The strategy
of defining a response enhanced biological sub-group is at the core of all NCRI
research strategy and indeed Pharma research strategy going forward. A NICE
position not supporting this approach may be difficult to maintain in the long term.
To summarise the outcome of the first Appraisal Committee meeting. The Appraisal
Committee felt that the use of trastuzumab in combination with cisplatin and
fluoropyrimidine chemotherapy was likely to offer a survival benefit over the current
UK standard of care in HER2 over-expressing gastric cancer. It was noted that the
survival gain was likely to be achieved without compromising quality of life. In
addition, no resource or infrastructure related barriers to the adoption of HER2
testing or the introduction of trastuzumab therapy were identified. Trastuzumab was
not recommended based on the committee’s conclusion that the estimated cost to
the NHS exceeded what could be considered a reasonable use of NHS resources. In
view of the concerns highlighted above it is felt that further evaluation of trastuzumab
is required in this indication where the benefits have been clearly defined.
Figure 1
CANCER TYPE
1971-72
2007
(predicted)
Bladder
Bowel - Colon
Bowel - Rectum
Brain
34.6%
22.6%
23.9%
5.7%
48.9%
50.4%
49.3%
9.4%
Breast (women)
Cervix
Hodgkin's lymphoma
Kidney
Larynx (men)
Leukaemia
Lung
38.9%
48.4%
49.0%
22.2%
50.5%
8.1%
3.2%
77.0%
63.0%
77.9%
43.5%
59.6%
33.2%
5.3%
Melanoma
Myeloma
Non-Hodgkin's lymphoma
Oesophagus
49.3%
5.3%
21.8%
3.6%
83.2%
17.1%
50.8%
10.0%
Ovary
Pancreas
18.0%
1.9%
35.4%
2.8%
Prostate
Stomach
20.4%
4.6%
68.5%
13.5%
Testis
Uterus
67.4%
55.2%
96.5%
74.5%
ALL CANCERS
23.7%
45.2%
Ten year relative survival of adults diagnosed with cancer in
England and Wales, 1971-2001
100
Testis
90
Melanoma
Hodgkin's lymphoma
80
Uterus
Breast
70
Cervix
Bladder
Percentage survival
Ten-year survival (%) for adults (15-99) diagnosed with
cancer during 1971-72 and predicted survival for adults
diagnosed in 2007
60
Larynx (m)
50
Prostate
All cancers
Colon
40
Kidney
Ovary
30
Leukaemia
20
Stomach
10
Brain
Oesophagus
Lung
Pancreas
0
Data for England and Wales
Source: Cancer Research UK.
1971-72
1980-81
1990-91
Period of diagnosis
2000-01
Figure 2.
FAMTX
Webb5,1997
Webb,
1997
5.7
ECF
8.9
CF
8.6
V3256,2006
V325,
2006
DCF
Dank,7,2008
Dank
2008
9.2
8.7
CF
IF
REAL II
II,4,2008
2008
9.0
ECF
9.9
EOX
11.2
CF/X
ToGA
ToGA8
(High HER2) CF/X+T
0
11.8
16.0
5Median survival10
in months
Median survival in months
15
FAMTX (5-FU, doxorubicin, methotrexate); ECF (epirubicin, cisplatin, 5-FU); CF (cisplatin, 5-FU); DCF
(docetaxel, cisplatin, 5-FU); IF (irinotecan, 5-FU); EOX (epirubicin, oxaliplatin, capecitabine).
Reference List
(1)
Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE.
Chemotherapy in Advanced Gastric Cancer: A Systematic Review and MetaAnalysis Based on Aggregate Data. J Clin Oncol 2006; 24(18):2903-2909.
(2)
Medical Research Council Oesophageal Cancer Working Party:
Surgical resection with or without preoperative chemotherapy in oesophageal
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(3)
Cunningham D, Allum WH, Stenning SP, Thompson JN et al.
Perioperative chemotherapy versus surgery alone for resectable
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(5)
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(6)
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(7)
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